Isoindolo {8 7,1,2-hij{9 quinolines

ABSTRACT

Isoindolo(7,1,2-hij)quinolines are provided having the structure   WHEREIN R5 can be hydroxyl, halogen, substituted amino, alkoxy, acyloxy, aroyloxy, substituted amido, and amino-subsituted amido; and R6 is hydrogen; and R5 and R6 can be taken together to form O; X, Y, R1, R2, R3 and R4 are as defined below; and which are anti-inflammatory agents, central nervous system depressants, inhibitors of cyclic AMP phosphodiesterase and sun-screening agents.

United States Patent [191 Levine Oct. 7, 1975 ISOINDOLO [7,1,2-HIJ1QU1NOLINES [75] Inventor: Seymour D. Levine, North Brunswick, NJ.

[73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

[22] Filed: Nov. 19, 1973 [2]] Appl. No.: 417,157

Related U.S. Application Data [62] Division of Ser. No. 2lS.l89, Jan. 3, I972, Pat. No.

[52] U.S. Cl. 260/289 C; 260/239', 260/247.5 GP; 260/268 BO; 260/283 S; 260/283 CN; 260/286 R; 260/288 CF; 424/258 [51] Int. Cl. C07!) 215/20 [58] Field of Search 260/287 R. 288. 289C [56] References Cited UNITED STATES PATENTS 3,351.600 ll/l967 Brack et al 260/288 R OTHER PUBLICATIONS ACS News, Apr. 3. 1972, p. 18 from Chemical and Engineering New". Burger, Medicinal Chemistry," I963, p. 42, col. l, par. 4, lnterscience Publishers,

Primary Examiner-Donald G. Daus Assistant ExaminerDavid E. Wheeler Attorney, Agent, or FirmLawrence S. Levinson; Merle J. Smith; Donald J. Barrack [57] ABSTRACT ls0indolo[7,l,2-hij1quinolines are provided having the structure R R2 R1 N 5 0 8 Claims, No Drawings [SOINDOLO 7,1 ,Z-HIJIQUINOLINES This is a divisional application of United States patent application Ser. No. 2l5,l89, filed Jan. 3, 1972, now US. Pat. No. 3,8l9,624, issued June 25, 1974.

This invention relates to isoindolo[7,l,2-hij] quinolines having the structure lA N.

substituted amido and aminosubstituted amido; R is hydrogen and R and R can be taken together to form =0; and acid-addition salts thereof where applicable.

R and R may be the same or different and represent hydrogen, lower alkyl, aryl and alkenyl. Furthermore, R and R can be taken together with N to form a heterocyclic ring.

The term lower alkyl as employed herein includes both straight and branched chain radicals of up to and including eight carbon atoms, for instance, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl and the like. The lower alkyl group can include substitutents such as aryl, halo, hydroxyl, alkoxy, amino or substituted amino.

The term halogen" includes, F, Cl, Br or I.

The term aryl as employed herein includes monocyclic carbocyclic aryl radicals, for instance, phenyl and substituted phenyl radicals, such as lower alkylor alkoxyphenyl (e.g., 0-, m-, or p-tolyl, ethylphenyl, butylphenyl and the like), di(lower alkyl)phenyl (e.g., 2,4-dimethylphenyl, 3,5-diethylphenyl, and the like, and corresponding alkoxy compounds), halophenyl (e.g., chlorophenyl, bromophenyl, iodophenyl and fluorophenyl o, mor p-nitrophenyl, dinitrophenyl (e. g., 3,5-dinitrophenyl, 2,6-dinitrophenyl, and the like), and trinitrophenyl (e.g., picryl), and aminophenyl, such as p-dimethylaminophenyl.

The acyl or aryl" portion of the acy1oxy" or aroyloxy group, respectively, is derived from a hydrocarbon carboxylic acid of less than 12 carbon atoms, which may be exemplified by the lower alkanoic acids (e.g., formic, acetic, propionic, butyric, valeric, trimethyl acetic and caproic acids), the lower alkenoic acids (e.g., acrylic, methacrylic, crotonic, 3-butenoic and senecioic acids), the monocyclic aryl-carboxylic acids (e.g., benzoic and toluic acids), the monocyclic aryllower alkanoic acids [e.g., phenacetic, B-phenylpropionic, a-phenylbutyric, and 5-( pmethylphenyhpentanoic acids], the cycloalkyl carboxylic acids (e.g., cyclobutane carboxylic acids, cyclopentane carboxylic acid and cyclohexane carboxylic acid), the cycloalkenyl carboxylic acids (e.g., 2- cyclobutene carboxylic acid and 3-cyclopentene carboxylic acid), the cyclopentene carboxylic acid), the cycloalkyl and cycloalkenyllower alkanoic acids [e.g., cyclohexaneacetic, a-cyclopentanebutyric, 2- cyclopenteneacetic and 3-(3-cyclohexene) pentenoic acids], and the like.

The term alkenyl includes mono-unsaturated straight chain or branched chain radicals of less than eight carbons corresponding to lower alkyl as defined above.

Examples of NRR" amino groups include monoor dilower alkyl-, arylalkyl-, lower alkylaryl-, alkenylor arylamino wherein lower alkyl and aryl are as defined herein, such as methylamino, ethylamino, isopropylamino, heptylamino, dimethylamino, diethylamino, ethylmethylamino, butylmethylamino, ethyl ipropylamino, allylamino, anilino, benzylamino, diphenylamino, naphthylamino, of N-methyl-N-phenylamino and the like.

NRR can be taken together to form a heterocyclic radical having the formula in which X represents NR 0, S or CH r represents 1, 2 or 3; R" represents hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, hydroxy-lower alkoxy|ower alkyl, di(lower alkyl)aminolower alkoxy-lower alkyl, lower alkylamino-lower alkyl, di-lower alkyl amino-lower alkyl, amino-lower alkyl; and R represents any of the R groups. These may be exemplified by piperidinyl; (lower alkyl)piperidinyl [e.g., 2-, 3- or 4-(lower alkyl)piperidinyl]; (lower alkoxy)piperidinyl; pyrrolidinyl; (lower alkyl)pyrrolidinyl; (lower alkoxy)pyrrolidinyl; piperazinyl; (lower alkyl)piperazinyl (e.g., N"-methylpiperazinyl); di(lower alkyl )piperazinyl; (lower alkoxy)piperazinyl; (hydroxylower alkyl)piperazinyl [e.g., N-(2-hydroxyethyl)- piperazinyl]; (lower alkanoyloxyalkyl)piperazinyl [e.g. N -(2-acetoxyethyl)piperazinyl1; (hydroxy-lower alkoxy-lower alkyl )piperazinyl [c.g. N"- 2-( 2- hydroxyethoxy)ethyl]piperazinyl1; di-(lower alkyl- )amino-(lower alkoxy-lower alkyl )piperazinyl [e.g., N" -[2-(Z-dimethylaminoethoxy)ethyl]piperazinyl];

homopiperazinyl; amino( lower alkyl)piperidinyl [c.g,

3-(aminoethyl)piperidinyl], lower alkylamino (lower alkyl )piperidinyl [e.g. 2-[ methylamino )ethyl piperidinyl], di-lower alkylaminoflower alkyl) piperidinyl [e.g., 4[(dimethylamino)methyl)]piperidinyl].

The term amido" as employed herein includes radicals of the structure.

lll

wherein R" can be lower alkyl, alkenyl, or aryl, substituted alkyl or substituted aryl, substituted with halogen, hydroxyl, alkoxy, amino or monoor disubstituted amino or a monocylic heterocycle such as pyridyl, furyl, thiazolyl, thienyl or pyrryl. The disubstitutcd amino substitutent of the alkyl may also form a five to seven membered hetcrocycle which may have up to two hetero atoms, such as morpholino, pyrrolidino or pipcridino.

The term amino-substituted amido" includes radicals of the structure Iv R R"N(CH L NH wherein n is l to l2 and (CH represent alkylene chains, that is, bivalent saturated straight or branched aliphatic groups, containing one to l2 carbons, corresponding to the above-mentioned lower alkyl groups and which may include lower alkyl and/or aryl side chains. Examples of such alkylene groups include methylene, ethylene, l-methylethylene, 2- methylethylene, tctramethylenc, propylene, trimethylene, hexamethylene, octamethylcne, decamethylcne, dodccamethylene, 3 methyldodecamethylene, dimethylethylcne, l-phenylethylene and the like.

The salts of the compounds of this invention include the acid-addition salts, particularly the non-toxic acidaddition salts. Acids useful for preparing the acidaddition salts, include inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid, and organic acids, such as oxalic, maleic, fumaric, tartaric, citric, pamoic, acetic, and succinic acid.

Compounds of formula I wherein R and R" are taken together to form --0 that is can be prepared by reacting a naphthostyril derivative of the structure with a cyclizing agent, such as polyphosphoric acid, in large excess, at a temperature within the range of from about 50 to about 200C and preferably from about 70 to about lC.

Compounds of formula I wherein R is hydroxyl and R is hydrogen, that is VII can be prepared by reducing compound V above by reacting it with an alkali metal borohydride, such as NaBlL, KBH or LiBH,

Compounds of formula I wherein R is halogen and R is hydrogen, that is Hal H VIII can be prepared by reacting compound Vll above with a halogcnating agent such as thionyl chloride, thionyl bromide, phosphorous trichloride or phosphorous tribromide.

Compounds of formula I wherein R is substituted amino R RN) and R is hydrogen, that is can be prepared by reacting compound Vlll above with an amine of the structure a 4 R 2 R1 alkyl-O can be prepared by refluxing compound VIII above with a lower alkanol.

Compounds of formula I wherein R is substituted amido, that is XII can be prepared by reacting compound VII above with a nitrile of the structure Xlll R"CN vary from a few minutes to several days. Generally, reaction times will be from about 10 minutes to about I00 hours. bower temperatures usually require longer reaction time.

While an excess of the nitrile is permissible, the nitrile and compound VII may also be employed in stoichiometric quantities, or with a slight excess of nitrile.

In the case of nitrilcs which are solid at room temperature, the reaction is preferably carried out in the presence of polar and non-polar solvents such as, for example, glacial acetic acid, acetic anhydride, di-n-butyl ether, chloroform, carbon tetrachloride, hexane and nitrobenzene.

A variety of acids may be used to carry out the reaction between compound VII and the nitrile. Examples of suitable acids are sulfuric, perchloric, phosphoric, polyphosphoric, formic, substituted sulfonic acids and boron trifluoride. In general, concentrated sulfuric acid is preferred.

Compounds of formula I wherein R is The reaction between the nitrile and compound VII conveniently takes place at about room temperature and at about atmospheric pressure. Operable temperatures, however, may vary from about C to about 80C, preferably from about 0C to about 60C and most preferably from about C to about C. Operable pressures may vary from about 0.2 atmosphere to about 5 atmospheres, preferably from about 0.5 atmosphere to about 2 atmospheres, and most preferably at about atmospheric pressure. The reaction time may that is wherein n is l to 4. can be prepared by reacting com- 3 pound Xll wherein R is (CH Hal, that is XVI H) can be prepared by reacting compound Vll with a carboxylic acid containing up to 12 carbons or an acid anhydride thereof or acyl or aroyl halide. Examples of l s such acids are set out hereinbefore.

Examples of starting naphthostyril derivatives which can be employed herein include, but are not limited to. the following set out in Table A below:

R' R" R" R X( position) Y( position) 0 H H H H H Br 4 c.,H 2 H CH H H H F 4) C 3 CH, C H H H H 1 4) H 4. CH CH, CH" H H H 3141 5 6 H H H H H N(CH,,)2 (4) H s. C;,H, H C H, H H Br (51 M. 7. H (3H,. H CHB H F(5) H s. H H CH (3H,, H 5) H 9. CDHH CsHii H H H ()CHn (5) CH 10. CH", H H H Br(fi) H OH ill H H H H F(6) H C H 12. (7 H H C 11,, H [(6) H H 13. CH H H CH3 Cl (6) H H 14 c n, CH CHl Cm? MH H H [5, (HM H H (Im m H g f. l6, H CH C ,H,, H FtH) H H 17. H C; H H u n H CH3 l8. C2H5 c Ht H CH3 im H H 19. H H H (,H (a) H (I ,H

with an amine of the structure X.

Compounds of formula I wherein R" is acyloxy or aroyloxy and R" is H. that is Other examples of naphthostyril derivative starting materials are set out in copending US. application Ser. No. 185,820. filed Oct. l, l97l entitled Naphthostyril Derivatives, and now abandoned.

Examples of other starting reactants such as R R"NH, are set out in the working Examples.

The compounds of this invention possess central nervous system modifying activity, particularly as depressants and are therefore useful as tranquilizers. They may be administered orally or parenterally in the form of tablets, capsules, elixers, injectables or the like by incorporating the appropriate dosage of the compound with carriers according to accepted pharmaceutical practice.

The dosage for various mammalian species would be form 25 to 250 mg. administered orally or parenterally once to several times daily, dependent upon the individual requirements of the recipient.

In addition, the compounds of the invention have been found to inhibit cyclic AMP phosphodiesterase, thereby providing an increase in the intracellular concentration of adenosine-3',5'-cyclic monophosphate. The administration of about 10 to 900 mg/kg/day, preferably about to 250 mg/kg, of the compounds of the invention in single or two to four divided doses in conventional oral or parenteral dosage forms such as those described above may be used to alleviate the symptoms of asthma.

Further, the compounds of the invention are useful as sunscreening agents.

The compounds of this invention are also useful as anti-inflammatory agents in warm blooded animals in a manner similar to indomethacin. They may be used to decrease joint swelling tenderness, pain and stiffness, in mammalian species, e.g., in conditions such as rheumatoid arthritis. A compound of formula 1 or a physiologically acceptable salt (when applicable) of the character described above may be compounded according to accepted pharmaceutical practice in oral dosage forms such as tablets, capsules, elixirs or powders for administration of about 100 mg to 2 gm per day, preferably 100 mg to 1 gm per day in two to four divided doses.

The following examples illustrate the present invention without, however, limiting the same thereto. All temperatures are expressed in C.

EXAMPLE 1 2,3-Dihydroisoindolo[ 7, l ,2-hij ]quinolinel ,5-dione A mixture of 260 mg of l,2-dihydro-2-oxobenz[cd]- indole-l-propionic acid in 12.5 ml of polyphosphorie acid is stirred and heated at 100 for 1 hour. The mixture is poured into water, stirred and extracted with chloroform. The chloroform extracts are washed with saturated sodium bicarbonate solution, 8% salt solution, dried and evaporated. Plate chromatography of the residue on neutral alumina using chloroform as the developing solvent gives a major yellow band which is eluted with ethyl acetate. Evaporation gives a residue which is crystallized from chloroform-isopropyl ether to give 1 17 mg of the title compound, m.p. 187188. Recrystallization from the same solvents gives the analytical sample, m.p. 187.5188.5.

Anal. Caled. for C 5HgNO2: C, 75.32; H, 4.06; N, 6.28. Found: C, 75.21; H, 4.32; N, 6.14.

EXAMPLE 2 9-Chloro-2,3-dihydroisoindolo[7, l ,2-hij ]quinoline- 1 ,5-dione Following the procedure of Example 1, but employ- 10 ing 6-chloro-1.2-dihydro-2-oxobenz[cdlindole-1- propionic acid as the starting material, there is obtained the title compound, m.p. 255.5256.5.

Anal. Caled. for CqHgClNOzl C, 65.25; H, 3.13; N, 5.44; Cl, 13.75. Found: C, 65.27; H, 3.40; N, 5.17; CI, 14.00.

EXAMPLE 3 2,3-Dihydrol -hydroxyisoindolo[ 7, l ,2-hij ]quinolin- 5( 1H one A solution of 1 17 mg of 2,3-dihydroixoindolo[7,1,2- hij]quinoline-l,5-dione in 5 ml of dioxane and 5 ml of methanol is treated with 30 mg of sodium borohydride and stirred at room temperature for 1 hour. The mixture is concentrated, diluted with water and extracted with chloroform. The extracts are washed with 8% salt solution, dried and evaporated. Plate chromatography of the residue on silica gel using chloroform-ethyl acetate as the developing solvent gives a major yellow band which is eluted with ethyl acetate. Evaporation gives a residue which is crystallized from chloroformisopropyl ether to give mg of the title compound, m.p. 162-163.5. Recrystallization from the same solvents gives the analytical sample, m.p. 163l64.

Anal. Calcd. for C H NO I C, 74.65; H, 4.92; N, 6.22. Found: C, 74.55; H, 5.18; N, 6.21.

EXAMPLE 4 9-Chloro-2,3-dihydro- 1 -hydroxyisoindolo[7, l ,2- hij]quinolin-5( lH)-one Following the procedure of Example 3, but employing 9-chloro-2,3-dihydroisoindolo[7,1,2-hij]quino1ine- 1,5-dione as the starting material, there is obtained the title compound, m.p. 240.524l.5.

Anal. Caled. for C H ClNO C, 64.75; H, 3.88; N, 5.40; C1, 13.65. Found: C, 64.54; H, 4.07; N, 5.19; Cl, 13.88.

EXAMPLES 1-Acetoxy-2,3-dihydroisoindolo[7, l ,2-hij lquinolin- 5(1H)-one A mixture of 200 mg of 2,3-dihydro-1- hydroxyisoindolo-[7,1,2-hij]quinolin-5( lH)-one in 1.5 ml of pyridine and 1.5 m1 of acetic anhydride is allowed to react overnight. The mixture is poured into ice-water and extracted with chloroform. The extracts are washed with 2N HCl, and 8% salt solution, dried and evaporated. The residue is crystallized from etherhexane to give 200 mg of the title compound, m.p. 106. Recrystallization from the solvents gives the analytical sample, l05106.

Anal. Caled. for C H NO C, 71.90; H, 4.90; N, 5.13. Found: C, 71.61; H, 5.08; N. 5.24.

EXAMPLE6 1-Chloro-2,3-dihydroisoindolo[7, l ,2-hij]quino1in- 5(1H)-one I A mixture of 1.0 g of 2,3-dihydro-1- hydroxyisoindolo[7,1,2-hij]quinolin-5( 1H )-one in 20 m1 of benzene is treated with 1.4 ml of thionyl chloride and stirred overnight. The mixture is diluted with water and the benzene layer separated. The benzene fraction is washed with water, 8% salt solution, dried and evaporated to give the title compound.

EXAMPLE7 l-Ethoxy-2,3-dihydroisoindolo[7,1,2hijlquinolin- 5(lH)-one A mixture of L66 g of l-chloro-2,3-

dihydroisoindolo[7,l ,2-hij]quinolin-5( lH )-one in 50 ml of ethanol containing l ml of triethylamine is refluxed for 2.5 hours. The solvents are evaporated, and the residue treated with water and extracted with chloroform. The chloroform extracts are washed with 8?! salt solution, dried and evaporated. The residue is crystallized from isopropyl ether to provide L38 g of the title compound, m.p. 95.5-96.5. Recrystallization from isopropyl ether gives the analytical sample, 9798.

Anal. Calcd. for c,,-H,,No.,: C, 75.87; H, 5.97; N, 5.53. Found: C, 75.95; H, 5.53; N, 5.3l.

EXAMPLE 8 2,3-Dihydrol -morpholinoisoindolo[ 7, l ,2- hij ]quinolin-5( H )-one EXAMPLE 9 2,3-Dihydrol -pyrrolidinoisoindolo[7, l ,2-hij1quinolin- 5( I )-one, hydrochloride Following the procedure of Example 8, but employing pyrrolidine as the amine, and converting the product to the hydrochloride salt, there is obtained the title compound, m.p. 292293d.

Anal. Calcd. for C H ClN O: C,68.68; H,6.()8; N,8.90; Cl,l l .26. Found: C,68.52; H,6.3l; N,8.65; Cl,l 1.52.

EXAMPLE l 1 Dimethylamino )-2,4-dihydroisoindolo[ 7, l ,2,- hij]quinolin-( lH)-one, hydrochloride Following the procedure of Example 9, but employing diethylamine as the amine, there is obtained the title compound, m.p. 23l .5232.5.

Anal. Calcd. for C H ClN Oz C,68.24; H,6.68; N,8.85; Cl,ll.l9. Found: C,67.90; H,6.74; N,9.l5; Cl,ll.23.

EXAMPLE I l l,9-Dichloro-2,3-dihydroisoind0lo[ 7, l ,2-hij ]quinolin- 5( lH)-one A solution of 500 mg of 2,3-dihydrolhydroxyisoindolo[7,l ,2-hij}quinolin-5( lH)-one in 5 ml of acetic acid is cooled in an ice-bath and treated with 0.25 ml of sulfuryl chloride. After 30 minutes at room temperature, an additional 0.25 ml of sulfuryl chloride is added and the mixture is stirred for L5 hour. The mixture is diluted with water and extracted with chloroform. The chloroform extracts are washed with 8% salt solution, dried and evaporated. Plate chromatography of the residue on silica gel using chloroform as the developing solvent gives a major yellow band which is eluted with ethyl acetate. Evaporation gives a residue which is crystallized from acetone-petroleum ether to afford mg of the title compound, m.p. l27l29. Recrystallization from the same solvents provides the analytical sample, m.p. l28l29.

Anal. Calcd. for C H Cl NO: C,60.47; H,3.23; N,5.04; Cl,25.50. Found: C,60.77; H,3.5l; N,4.98; Cl,25.62.

EXAMPLE l2 9-Chloro-2,3-dihydrol -pyrrolidinoisoindolo[ 7,] ,2- hij ]quinolin-5( lH)-one, hydrochloride A mixture of 3.1 g of l,9-dichloro-2,3- dihydroisoindolo[7, l ,2-hij]quinolin-5( lH)-one in 50 ml of dioxane and 10 ml of pyrrolidine is refluxed overnight and evaporated. The residue is treated with 2N sodium hydroxide solution and extracted with chloroform. The chloroform extracts are washed with 8% salt solution, treated with charcoal, filtered and dried. The free base is dissolved in dimethoxyethane treated with methanolic HCl and the solid collected by filtration to afford 1.53 g of the title compound, m.p. 308309d. Recrystallization from ethanol provides the analytical sample, m.p. 3 l 2-3 l4d.

Anal. Calcd. for C H C| N 0Z C,6l.90l H,5,l9; N,8.02; Cl,20.34. Found: C,62.l8; H,5.36; N,7.87; Cl,20.54.

EXAMPLE I 3 9-Chloro-2,3-dihydrol -morpholinoisoindolo[ 7 l ,2- hij ]quinolin-5( l H l-one, hydrochloride Following the procedure of Example 12, but employing morpholine as the base, there is obtained the title compound, m.p. 277279d.

Anal. Calcd. for C H Cl N O C,59.l8; H,4.97; N,7.66; Cl.l9.l4. Found: C,59.0l; H,5.2l; N,7.37; Cl,l9.25.

EXAMPLE I 4 l-Acrylamido-2,3-dihydroisoindolol 7,1 ,2-hij ]quinolin- S( lH )-one An ice-bath cooled suspension of 500 mg of 2,3- dihydrol -hydroxyisoindolo[7 l ,2-hij ]quinolin- 5( lH)-one in 5 ml of acrylonitrile is treated dropwise with 1.5 ml of concentrated sulfuric acid. The reaction mixture is stirred at room temperature for 2.5 hours, diluted with water and extracted with chloroform. The chloroform extracts are washed with 8% salt solution, dried and evaporated. Crystallization from chloroform gives 442 mg of the title compound, m.p. 234235. Plate chromatography of this material on silica gel using chloroform-ethyl acetate l:l as the developing solvent gives a major yellow band, which is eluted with ethyl acetate. Evaporation and crystallization of the residue from chloroform gives the analytical sample, m.p. 237-238.

Anal. Calcd. for C I-N 0 C,73.36; H,5.07; N,l0.()7. Found: C,73.3l; H,4.98; N,l0.03.

EXAMPLE 1 lAcetamido-2,3-dihydroisoindolo[ 7 l ,2-hij ]quinolin- 5( l H )one Following the procedure of Example l4, but employing acetonitrile, there is obtained the title compound, m.p. 253254.

Anal. Calcd. for C H N O C,72. l6; H,5.30; N,lO.52. Found: C,7l89; H,5.58; N,l().43.

EXAMPLE l6 l-Benzamido-2,3-dihydroisoindolo[ 7, l ,Z-hij ]quinolin- 5( l H )-one Following the procedure of Example l4, but employing benzonitrile, there is obtained the title compound, m.p. 26l5262.5.

Anal. Calcd. for C ,H, N O C,76.8l; N,8.53. Found: C,76.76; H,4.95; N,8.46.

EXAMPLE 1? l-( 3-Bromopropionamido )-2,3 dihydroisoindolo[ 7,1 ,2-hij]quinolin-5( lH)-one Following the procedure of Example 14, but employing 3bromopropionitrile, there is obtained the title compound, m.p. 291-2l9.5.

Anal. Calcd. for C H BrN- O- C,56.85; H,4.2l; N,7.80; Br,22.25. Found: C,57.10; H,4.34; N,7.73; Br,22.45.

EXAMPLE l8 2 3-Dihydrol 3-morpholinopropionamido isoindolol 7, l .2-hij ]quinolin-5( l H )-one Example Anal. Calcd. for C ,H ;,N O;,: C,69.02; H,6.34; N,l L50. Found: c.6922; H,6.48; N,l L66.

EXAMPLE l9 2,3-Dihydrol 3-( pyrrolidinyl )propionamido]isoindolo[7, l ,2- hij]quinolin-5( lH)-one Following the procedure of Example 18, but employing pyrrolidine as the amine, there is obtained the title compound, m.p. 2l42l5.

Anal. Calcd. for C ,H ;;N;,O C,72.l8; H,6.63; N.l2.03. Found: (f/2.34; H.688; N,l2.07.

EXAMPLE l-[ 3-( Diethylamino)propionamido]-2,3- dihydroisoindolo[ 7 l ,Z-hij ]quinolin-5( l H )-one, hydrochloride Following the procedure of Example 1 8, but employing diethylamine as the amine and converting the product to its hydrochloride salt, there is obtained the title compound, m.p. 238-239.

Anal. Calcd. for c H -ClN O C,65.08; H,6.75; N,10.83; Cl,9.l4. Found: 11,702; J Cl,9.08.

EXAMPLES 21 TO 30 Following the procedure of Example 1, but employing the naphthostyril derivative shown in column 1 Table l in place of l.2-dihydro-2-oxobenz-[cd]-indolel-propionic acid, the product shown in column 2 is obtained.

TABLE I No. Q R' R-' R" R" x Y R' R R" R x Y 21 CH CH H H H H H 22 H CJH1 H H CEHF, (z-Br H As per Column l 23 (3H, CH CH3 CH3 CH3 H 4-O'ZH; 24 (,H,I (3H7 CH CH CH;, 6C"H5 H 25 H H H C4H9 H H 4N(CH,-|)2 2r C;,H" H H H H H 5OCH:, 27 CH1 z n CH3 g CH1; H 4-Br 28 H H H CH3 H H 5F 29 CH" CH3 CH3 H H 6OCH,1 H 30 H H H H H 6-F H A solution of 650 mg of l-(3-bromopropionamido)- EXAMPLES 3] TO 2 Y1 i 7. ,2-hi' uinolin-S 1H -one in 3 dihydn lso ndolo[ l )]q Examples 31 to 4O 15 ml of ethanol and 1.3 ml of morpholme IS refluxed for 2 hours. The mixture is concentrated and the solid Following the procedure of Example 3, but substitutcollected by filtration to give 458 mg of the title compound m.p. 20()2()4. Recrystallization from chloroform-isopropyl ether gives the analytical sample, m.p.

ing the ketones prepared in Examples 21 to 30 for the ketone used in Example 3, the hydroxy compound shown in Table ll below is obtained.

TABLE ll Example No Product Following the procedure of Example 6, but substitut- 2,3-dihydrol -hydroxyisoindolo[ 7. l ,2- hij]quinolin-5( lH)-one, the compounds prepared in Examples 31 to 40. the product shown below in Table ing for lll is obtained.

TABLE II] Following the procedure of Example 5. but substituting the l-hydroxy compound prepared in Example 31 to 40 and the acid, acid anhydride, 0r acyl or aroyl halide shown in column l of Table IV below, the product 35 shown in column 2 is obtained.

Example Nu.

TABLE IV R l o R A N O 5 A R -CO Acid Anhydride Example or Acid or Aroyl X Y No. or Acyl Halide 59 CH CH H H 9OCH;, H

EXAMPLES 6] TO 70 3s EXAMPLES 7l TO 80 Following the procedure of Example 7, substituting for the halogen derivative starting material of Example Following the procedure of Example 8, but substitut- 7, the halogen derivatives prepared in Examples 41 to ing the halonaphthostyril starting material prepared in 50 and employing the alkanols set out in Column 1 of Examples 4| to 50 and the amine or hcterocyclic reac- Table V below, the product shown in Column 2 of 40 tant shown in column 1 ofTable Vl below,the product Table V is obtained. shown in Column 2 is obtained.

Table V Example Column 1 Column 2 Alkzmol R 3 ROH 2 tuting the 2,3-dihydro-l-hydroxyis0indolo[7.l,2- tuting as starting materials the halogennaphthostyril jlq lmp un of amples 3! t0 derivatives shown in column I of Table Vlll below 40 and the nitrile shown in column I of Table VII, the (prepared by reacting any of the compounds of Exam- PrO I-I I hown in Column 2 i8 Ob ined- 4 ples 3, 4 and 31-40 with a nitrile of the structure TABLE VI] HaI-(CH- ),,CN 4. The compound having the name 9-chIor0-2,3-

dihydro- I -hydroxyisoindolo[ 7, I ,2-hij lquinol'mwhere n is I to 4 as per the procedure of Examples I4 5( IH)-nc. and 81 to 90) and the amine shown in column 2, the 5. The compound having the name l-acetoxy-l3- product shown in column 3 is obtained. dihydroisoindolo[7,l ,2-hij]quinoIin-5( IH)-one.

TABLE VIII ('ulumn I 3 Column 3 R 3 1 n R Ex, Nu, Hill 11 R R R R X Y HNRR" R"R"N nRR R"R"X Y 9| CI I (H H H H H H HN(C H ,)CH; As per AsFer E olumn I Column 9: Br 2 .H H H c Hr, 9Br 4H HQ 2 )3 Br 3 CH CH, CH CH,, H 7- CH,.,0 HQ 94 (I 4 (3H: CH1 II T CH1; !I H HN 95 2 H H C.H,, H H 7(CH;.)-,N HN (CH2). ,OH

9h Br 1 H H H H H 8-OCH HNHC4HU 97 Br 2 C CH,. C2H.-. CH3 H 9x CI 2 H H CH; H H 8-F NlCHMQ J. 99 Br 2 CH CH H H 9-0CH H H@ CH,CH.,O mo Cl 1 H H H H '-JF H HG What is claimed is: 6. The compound having the name I-chIoro-2,3- I. The compound having the name 2,3- dihydr0isoindoIo[7,I,2-hij]quinoIin-5(II-I)-one. dihydroisoindolo[7,l,2-hij]quinoIine-I,S-dione. 7. The compound having the name I-eth0xy-2,3-

2. The compound having the name 9-chIoro-2,3- dihydr0isoindoIo[7,I,2-hij]quinoIin-5(IH)-one. dihydroisoindolo[7,l,2-hij]quinolinel ,S-dione. 8. The compound having the name I,9-dichIoro-2 3- 3. The Compound having the name 2,3-dihydro-l- 40 dihydroisoindolo[7,l,2hij]quinoIin-5( IH)-0ne hydroxyisoindolo[7,l,2hij]quinoIin-5(IH)-one.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 1 3,910 ,926

DATED I October 7, 1975 KNVENTUMS) Seymour D. Levine it is cerimed thu! mar appear :r; thv :Jmveidenlifked patent and that said LuHers Patent are hereby conected as shown beiow Column 9, line 12, "form" should read --from--.

Column 9, line 61, should read C Column 11, line 48, "2,4" should read -2,3-

Column 13, line 26 "2912l9. 5 should read -2l9-2l9. 5-.

Column 14, line 31, the word "of" should follow "column 1" Signed and Scaled this twenty-third Day of March 1976 [SEAL] A ttesr:

RUTH C. MASON C. MARSHALL DANN Atlesling Officer (ummissinner nf'lalenls and Trademarks 

1. THE COMPOUND HAVING THE NAME 2.3-DIHYDROISOINDOLO(7.1.2-HIJ)QUINOLINE-1.5-DIONE.
 2. The compound having the name 9-chloro-2,3-dihydroisoindolo(7, 1,2-hij)quinoline-1,5-dione.
 3. The compound having the name 2,3-dihydro-1-hydroxyisoindolo(7,1,2hij)quinolin-5(1H)-one.
 4. The compound having the name 9-chloro-2,3-dihydro-1-hydroxyisoindolo(7,1,2-hij)quinolin-5(1H)-one.
 5. The compound having the name 1-acetoxy-2,3-dihydroisoindolo(7,1,2-hij)quinolin-5(1H)-one.
 6. The compound having the name 1-chloro-2,3-dihydroisoindolo(7, 1,2-hij)quinolin-5(1H)-one.
 7. The compound having the name 1-ethoxy-2,3-dihydroisoindolo(7, 1,2-hij)quinolin-5(1H)-one.
 8. The compound having the name 1,9-dichloro-2,3-dihydroisoindolo(7,1,2-hij)quinolin-5(1H)-one. 